Phenyl pyrimidine amine derivatives are known from the patents WO 9509851, WO 9509853,
EP0588762, WO 9509847, WO 9903854, and EP-B-0-564 409 as effective compounds for treatment of tumors.
For example in WO 9509851 compounds of the general formula II are disclosed
wherein
R1 is a substituted cyclic radical, the cyclic radical being bonded to a ring carbon atom in each case and being selected from phenyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned cyclic radical being selected from one or more of the groups halogen, cyano, carbamoyl, —C(═O)—OR3, —C(═O)—R4, —SO2-N(R5)-, —N(R7)-R8, —OR9 and fluorine substituted lower alkyl, wherein R3, R4, Rs, R6, R7, R8 and Rg are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino; and
R2 is selected from halogen, cyano, carbamoyl, —C(═O)—OR10, —C(═O)—R11, —SO2-N(R12)-R13, —N(R14)-R15, —OR16 and fluorine-substituted lower alkyl, wherein R10, R11, R12, R13, R14, R1S and R16 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino, or a salt of such a compound having at least one salt-forming group.
In WO 9509853, N-phenyl-2-pyrimidineamine derivative compounds of the general formula III are disclosed

An N-phenyl-2-pyrimidineamine derivative of formula III wherein R0 is hydrogen, halogen, lower alkoxy or lower alkyl,
R1 is
a) N-(amino-lower alkyl)-carbamoyl,
b) N-(hydroxy-lower alkyl)-carbamoyl,
c) hydrazino,
d) cyclohexyl-amino that is unsubstituted or substituted by amino,
e) piperazinyl that is unsubstituted or substituted by amino-lower alkyl,
f) morpholinyl, or
g) lower alkylamino that is substituted by morpholinyl, hydroxy-lower alkylamino, cyano, imidazolyl, guanidyl, amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl, formylpiperazinyl, prolylamido or by a radical of the formula H2 N—CH(R)—C(═O)—NH— wherein R is hydrogen, C1-C4 alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, and
R2 is C1-C6 alkyl, C1-C3 alkoxy, chlorine, bromine, iodine, trifluoromethyl, hydroxy, phenyl, amino, mono(C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, C2-C4 alkanoyl, propen-yloxy, carboxy, carboxy-methoxy, ethoxycarbonyl-methoxy, sulfanilamido, N,N-di-(C1-C3 alkyl)sulfanilamido, N-methyl-piperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethyl-benzyl or a radical of one of the formulae:
—CO2 R3, —NH—C(═O)—R3, —N(R3)-C(═O)—R4, —O—(CH2)n-N(R3)-R4, —C(.dbd.O)—NH—(CH2)n-R4@a, —C(═O)—NH—(CH2)n-N(R3)-R4, —CH(CH3)-NH—CHO, —C(CH3).dbd.N—OH, —C(CH3)═N—O—CH3, —CH(CH3)-NH2, —NH—CH2-C(═O)—N(R3)-R4, wherein R3 and R4 are each independently of the other C1-C3 alkyl, R4@a is hydroxy, amino or imidazolyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 2 or 3, R5 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, chlorine, bromine, iodine or trifluoromethyl, R6 is 1H-imidazol-1-yl or morpholinyl and R7 is C1-C3 alkyl or is phenyl that is unsubstituted or mono-substituted by C1-C3 alkyl, halogen or by trifluoromethyl, or a salt thereof. An N-phenyl-2-pyrimidineamine derivative of formula III wherein R0 is hydrogen, halogen, lower alkoxy or lower alkyl,
R1 is
a) N-(amino-lower alkyl)-carbamoyl,
b) N-(hydroxy-lower alkyl)-carbamoyl,
c) hydrazino,
d) cyclohexyl-amino that is unsubstituted or substituted by amino,
e) piperazinyl that is unsubstituted or substituted by amino-lower alkyl,
f) morpholinyl, or
g) lower alkylamino that is substituted by morpholinyl, hydroxy-lower alkylamino, cyano, imidazolyl, guanidyl, amino, lower alkanoylamino, lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy, piperazinyl, lower alkanoyl-piperazinyl, formylpiperazinyl, prolylamido or by a radical of the formula H2 N—CH(R)—C(═O)—NH— wherein R is hydrogen, C1-C4 alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, mercaptomethyl, 2-methylthio-ethyl, indol-3-yl-methyl, phenyl-methyl, 4-hydroxy-phenyl-methyl, carbamoyl-methyl, 2-carbamoyl-ethyl, carboxy-methyl, 2-carboxy-ethyl, 4-amino-butyl, 3-guanidyl-propyl or R is 1H-imidazol-4-yl-methyl, and R2 is C1-C6 alkyl, C1-C3 alkoxy, chlorine, bromine, iodine, trifluoromethyl, hydroxy, phenyl, amino, mono(C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, C2-C4 alkanoyl, propen-yloxy, carboxy, carboxy-methoxy, ethoxycarbonyl-methoxy, sulfanilamido, N,N-di-(C1-C3 alkyl)sulfanilamido, N-methyl-piperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethyl-benzyl or a radical of one of the formulae:
—CO2 R3, —NH—C(═O)—R3, —N(R3)-C(═O)—R4, —O—(CH2)n-N(R3)-R4, —C(═O)—NH—(CH2)n-R4@a, —C(═O)—NH—(CH2)n-N(R3)-R4, —CH(CH3)-NH—CHO, —C(CH3)═N—OH, —C(CH3)=N—O—CH3, —CH(CH3)-NH2, —NH—CH2-C(═O)—N(R3)-R4, wherein R3 and R4 are each independently of the other C1-C3 alkyl, R4@a is hydroxy, amino or imidazolyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 2 or 3, R5 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, chlorine, bromine, iodine or trifluoromethyl, R6 is 1H-imidazol-1-yl or morpholinyl and R7 is C1-C3 alkyl or is phenyl that is unsubstituted or mono-substituted by C1-C3 alkyl, halogen or by trifluoromethyl, or a salt thereof.
EP0588762 eidem., U.S. Pat. No. 5,516,775 compounds of the general formula IV are disclosed
wherein R1 is hydrogen or C1-C3 alkyl, R2 is hydrogen or C1-C3 alkyl, R3 is 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-methyl-3-pyridyl, 4-methyl-3-pyridyl, 2-furyl, 5-methyl-2-furyl, 2,5-dimethyl-3-furyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-phenothiazinyl, 4-pyrazinyl, 2-benzofuryl, N-oxido-2-pyridyl, N-oxido-3-pyridyl, N-oxido-4-pyridyl, 1H-indol-2-yl, 1H-indol-3-yl, 1-methyl-1H-pyrrol-2-yl, 4-quinolinyl, 1-methyl-pyridinium-4-yliodide, dimethylaminophenyl or N-acetyl-N-methylaminophenyl, R4 is hydrogen, C1-C3 alkyl, —CO—CO—O—C2 H5 or N,N-dimethylaminoethyl, at least one of R5, R6, R7 and R8 is C1-C6 alkyl, C1-C3 alkoxy, chloro, bromo, iodo, trifluoromethyl, hydroxy, phenyl, amino, mono-(C1-C3-alkyl)amino, di(C1-C3 alkyl)amino, C2-C4 alkanoyl, propenyloxy, carboxy, carboxymethoxy, ethoxycarbonylmethoxy, sulfanilamido, N,N-di(C1-C3 alkyl)sulfanilamido, N-methylpiperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethylbenzyl or a radical of one of the formulae:
—CO2 R, —NH—C(═O)—R, —N(R)—C(═O)—R,
—O—(CH2)n-N(R)—R, —C(═O)—NH—(CH2)n-N(R)—R, —CH(CH3)-NH—CHO, —C(CH3)═N—OH,
—C(CH3)═N—O—CH3, —C(CH3)-NH2, —NH—CH2-C(═O)—N(R)—R,
—(CH2)m-R10, —X—(CH2)m-R10 or wherein R is C1-C3 alkyl, X is oxygen or sulfur,
m is 1, 2 or 3,
n is 2 or 3, R9 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, chloro, bromo, iodo or trifluoromethyl, R10 is 1H-imidazol-1-yl or morpholinyl, and R11 is C1-C3 alkyl or unsubstituted phenyl or phenyl which is monosubstituted by C1-C3 alkyl, halogen or trifluoromethyl, and the other substituents R5, R6, R7 and R8 are hydrogen, or a pharmaceutically acceptable salt thereof.
In EP 0564 409 compounds of the general formula V are disclosed
Wherein
R1 is pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated or acylated, 1H-indolyl or 1H-Imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen,
R2, R3 are each independently of the other hydrogen or lower alkyl, one or two of the radicals R4, R5, R6, R7 and R8 are each nitro, fluoro-substituted lower alkoxy or a radical of theformula (Va)—N(R9)—C(═X)—(Y)n—R10  (Va)Wherein
R9 is hydrogen or lower alkyl,
X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino,
Y is oxygen or the group NH,
N is 0 or 1 and
R10 is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or hetero-cyclicaliphatic radical,
And the remaining radicals R4, R5, R6, R7 and R8 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterified hydroxyl, free, alkylated or acylated amino or free or esterified carboxy, or a salt of such a compound having at least one salt-forming group.
In WO 9509847, N-phenyl-2-pyrimidineamine derivative of the general formula VI are disclosed
wherein
R1 is naphthyl, fluorenyl, anthracenyl or a substituted cyclic radical, the cyclic radical being bonded to a ring carbon atom in each case and being selected from phenyl, pyridyl, 1H-indolyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned phenyl radical being selected from hydroxy, halogen, nitro, cyano, unsubstituted or halogen-substituted lower alkoxy, from a radical of formula VIaC(═O)—(O)m-R3  (V1a)wherein m is 0 or 1 and
R3 is hydrogen, benzyl, lower alkyl or amino-lower alkyl wherein the amino group is free, lower alkylated or lower alkanoylated, from a radical of formula m —C(═O)—N(R4)R5 (V1b) wherein
R4 and R5 are each independently of the other hydrogen or unsubstituted or amino- or hydroxy-substituted lower alkyl, from a radical of formula VIc—SO2-N(R6)R7  (VIc) wherein
R6 and R7 are each independently of the other hydrogen, lower alkyl or amino-lower alkyl, or wherein
R6 and R7 together form the bivalent radical —(CH2)2-NH—(CH2)2-, and from radical of formula VId—N(R8)R9  (VId) wherein
R8 and R9 are each independently of the other lower alkyl, or wherein
R8 is hydrogen and R9 is amino or amino-cyclohexyl, or is lower alkyl that is substituted by imidazolyl, guanidyl, lower alkylamino-carbonylamino, amidino, di-loweralkylamino-cyclohexyl, piperazinyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy or by formylpiperazinyl, and the substituents of the other above-mentioned cyclic radicals being selected from hydroxy, halogen, cyano, amino-lower alkyl, unsubstituted or halogen-substituted lower alkoxy, phthalimido-substituted lower alkyl, from a radical of the above-mentioned formulae VIa, m or VIc and from a radical of formula VII—N(R10)R11  (VII)wherein R10 and R11 are each independently of the other hydrogen or lower alkyl, or wherein R10 is hydrogen and
R11 is amino or amino-cyclohexyl, or is lower alkyl substituted by amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, imidazolyl, guanidyl, lower alkylamino-carbonylamino, amidino, di-lower alkylamino-cyclohexyl, piperazinyl, formylpiperazinyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-hydroxy-carbamoyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy or by glycylamido; and
R2 is nitro, fluorine-substituted lower alkoxy or a radical of formula VIII—N(R12)-C(═X)—(Y)n-R13  (VIII)wherein
R12 is hydrogen or lower alkyl,
X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino,
Y is oxygen or the group NH, n is O or 1, and
R13 is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromaticaliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical, or a salt of such a compound having at least one salt-forming group.
Furthermore EP0564409 discloses the use of said compounds in the treatment of artherosclerosis. The patent WO9903854 describes the use of pyridyl pyrimidine amine derivatives, especially of Gleevec™, the Novartis compound CGP57148 of the formula IX, as tyrosine kinase inhibitors in cancer treatment. The IC50 value reported for Gleevec™, is 38 nano molars (nm).

In the recent patent WO 0222597 dated Nov. 9, 2001 of Novartis, compounds of the formula (X) have been disclosed wherein:
Ri is pyrazinyl; 1-methyl-1H-pyrrolyi; amino- or amino-lower alkyl-substituted phenyl, wherein the amino group in each case is free, alkylated oracylated; 1H-indolyl or 1H-imidazolyl bonded at a five-membered ring carbon atom; or unsubstituted or lower alkyl substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, R2 and R3 are each independently of the other hydrogen or lower alkyl, one of the radicals R4, R5, R6, R7 and R8 is a radical of formula 11 —N(R9)-C(═X)—(Y)n-R10 wherein
Rg is hydrogen or lower alkyl,
X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or 0-lower alkyl-hydroximino, Y is oxygen or the group NH, n is 0 or 1 and
R10 is phenyl which is a) substituted by a radical selected from the group consisting of amino; mono- or di lower alkylamin; lower alkanoylamino; formyl; lower alkoxy-carbonyl; and lower alkyl which is substituted by amino, mono- or di-lower alkylamin or loweralkanoylamino, or b) substituted by an unsubstituted or substituted radical selected from the group consisting of benzylamino; benzoylamino; pyrrolidinyl; piperidyl; piperazinyl; piperazinyl-carbonyl; morpholinyl; and lower alkyl substituted by benzylamino, benzoylamino, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, the substituents of said substituted radical being selected from the group consisting of cyano; lower alkyl; hydroxy- or amino-substituted lower alkyl; trifluoromethyl; hydroxy; lower alkoxy; lower alkanoyloxy; amino; mono- or di-lower alkylamin; lower alkanoylamino; benzoylamino; carboxy; lower alkoxycarbonyl and halogen, and c) optionally further substituted by one or more radicals selected from the group consisting of cyano; lower alkyl; hydroxy- or amino-substituted lower alkyl; trifluoromethyl; hydroxy; lower alkoxy; lower alkanoyloxy; amino; mono- or di-lower alkylamin; lower alkanoylamino; benzoylamino; carboxy; lower alkoxycarbonyl and halogen, with the proviso that RIO is not (4-methyl-piperazinyl)-methylphenyl, and the remaining radicals R4, R5, R6, R7 and R8 are each independently of the others hydrogen; lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidyl, pyrrolidinyl or morpholinyl; lower alkanol; trifluoromethyl; free, etherified or esterified hydroxy; free, alkylated oracylated amino; or free or esterified carboxy, or a salt of such a compound having at least one salt-forming group.
It is very well known that phenyl amino pyrido pyrimidines falling under the above mentioned categories are found to be very useful for the treatment of Bcr-abl positive cancer and tumor diseases, such as leukemias [especially Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia, where especially apoptotic mechanisms of action are found]. Consequently interest and attention are being given for developing more new molecules falling within above mentioned categories of compounds.
With the above objectives in view we continued our R & D in the above mentioned directions and have filed applications for patents both for new molecules as well as for the improved processes for the preparation of such molecules
Therefore, the main objective of the present invention is to provide novel phenyl amino pyrido pyrimidines of general formula (I) defined above and their pharmaceutically acceptable salts
Another objective of the present invention is to provide novel phenyl amino pyrido pyrimidines of general formula (I) defined above and their pharmaceutically acceptable salts which have IC50 values in the range 0.1 to 10.0 nm
Yet another objective of the present invention is to provide novel phenyl amino pyrido pyrimidines of general formula (I) and their pharmaceutically acceptable salts which are useful for the treatment of CML
Still another objective of the present invention is to provide a process for the preparation of novel phenyl amino pyrido pyrimidines of general formula (I) defined above and their pharmaceutically acceptable salts
Further objective of the present invention is to provide a pharmaceutical composition containing the novel phenyl amino pyrido pyrimidines of general formula (I) and their pharmaceutically acceptable salts useful for the treatment of CML
Still another objective of the present invention is to provide a process for the preparation of pharmaceutical composition containing novel phenyl amino pyrido pyrimidines of general formula (I) defined above and their pharmaceutically acceptable salts
Still another objective of the present invention is to provide novel intermediates useful for the preparation of novel compounds of the formula I defined above
Yet another objective of the present invention is to provide processes for the preparation of novel intermediates useful for the preparation of novel compounds of the formula I defined above
Accordingly, the present invention provides phenyl amino pyrido pyrimidines of general formula (I)

Wherein the symbols have the following meanings
Series ASeries BX = CHX = Nn = 1, 2n = 1R = H, MeR = H, MeY = 0(zero), S, SO,Y = 0(zero), S,SO2SO, SO2and the pharmaceutically acceptable salts thereof
The trifluoro methyl group in the above compounds is preferably bonded to the phenyl/pyridinyl at position 3 (when n=1) and when two such groups are present, they are preferably bonded at positions 3,5 (when n=2)
Special preference is given to compounds of the general formula (I) wherein R represents methyl group and the trifluoromethyl group is present in position 3 of the phenyl/pyridinyl ring (n=1, Series-A, Series-B) and when two such groups are present, bonding at position 3,5- is preferred (n=2, Series-A).
Very special preference is given to compound(s) of general formula (I) where in R represents a methyl group and the trifluoromethyl group is present in position 3 and position 3,5- of the phenyl ring (n=1; and 2, Series-A)
The above mentioned compounds are new as they have not been reported in the literature
The compounds of the formula (I) form pharmaceutically acceptable salts. For example salts are formed with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, (or) with suitable organic carboxylic (or) sulfonic acids for example aliphatic mono- (or) dicarboxylic acids, such as trifluoro acetic acid acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid citric acid (or) oxalic acid (or) amino acids such as arginine (or) lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy benzoic acid, 2-acetoxy benzoic acid, salicylic acid aromatic aliphatic carboxylic acids, such as nicotinic acid aliphatic sulfonic acids, such as methane sulfonic acid and aromatic sulfonic acids like for example benzene and 4-toluene sulfonic acids.
However, only pharmaceutically acceptable non toxic salts are used for the therapeutic purposes, and those salts are therefore preferred.
According to another embodiment of the invention there is provided a process for the preparation of novel phenyl amino pyrido pyrimidines of the formula I,
where the symbols have the meanings given below and their pharmaceutically acceptable acid addition salts which comprises
(i) condensing 4-methyl-3-nitroaniline of the formula (XI)
wherein R represents hydrogen or methyl with trifluoro methyl aroyl chlorides of the formula (XII),
n represents 1 or 2 and x represents N or H in the presence of chloro hydrocarbon solvent and a base at a temperature in the range of 30 to 40 Deg C. to yield the novel intermediate nitro trifluoromethyl aroyl amides of the formula (XIII)

where R and n have the meanings given above                (ii) Reducing the resulting novel compounds of the formula (XIII) using a metal—acid reducing agent at a temperature in the range of 0-5° C. to yield the novel intermediate amino trifluoromethyl aroyl amides of the formula (XIV)        

where R & n have the meanings given above.                (iii) condensing the compounds of the formula (XIV) with cyanamide (CNNH2) at a temperature in the range of 60 to 95° C. in the presence of polar solvent and an inorganic acid to yield the novel intermediate salts of guanidino trifluoromethyl aroyl amides of formula (XV)        

where R and n have the meanings given above and                (iv) condensing the novel compounds of the formula (XV) with a compound of formula (XVI) in the presence of a base and at a temperature in the range of 30 to 40 Deg C. to yield the novel compounds of general formula (I) where R, n, X are as defined above and if desired converting the novel compounds of the formula I into pharmaceutically acceptable salts by conventional methods        
The above defined process is shown in the Scheme I given below

According to another embodiment of the invention there is provided a process for the preparation of novel nitro trifluoromethyl aroyl amides of the formula (XIII)

Useful as an intermediate for the preparation of novel compound of the formula I which comprises                condensing 4-methyl-3-nitroaniline of the formula (XI)        
wherein R represents hydrogen or methyl with trifluoro methyl aroyl chlorides of the formula (XII),
wherein n represents 1 or 2 and x represents N or H in the presence of chloro hydrocarbon solvent and a base at a temperature in the range of 30 to 40 Deg C. to yield the novel intermediate nitro trifluoromethyl aroyl amides of the formula (XIII)

According to another embodiment of the invention there is provided a process for the preparation of novel amino trifluoromethyl aroyl amides of the formula (XIV)

where R & n have the meanings given above.
useful for the preparation of novel compounds of the formula I which comprises
reducing the r novel compounds of the formula (XIII) using a metal-acid reducing agent at a temperature in the range of 0-5° C. to yield the novel compounds of the formula XIV
According to another embodiment of the invention there is provided a process for the preparation of novel salts of guanidino trifluoromethyl aroyl amides of formula (XV)
where R and n have the meanings given above, useful as an intermediate for the preparation of new compounds of the formula I which comprises condensing the compounds of the formula (XIV) with cyanamide (CNNH2) at a temperature in the range of 60 to 95° C. in the presence of polar solvent and an inorganic acid to yield the novel intermediate of formula (XV)
In a preferred embodiment of the invention, the chloro hydrocarbon solvent used in step (i) may be selected from—Chloroform, Methylene chloride or ethylene chloride, preferably chloroform
The base used may be selected from triethyl amine, dipropyl amine or diisopropyl amine preferably triethyl amine. The temperature may be preferably in the range of 30 to 40-Deg C.
In another embodiment the metal—acid reducing agent used in step (ii) for reducing the novel compound of the formula-XII may be selected from stannous chloride/Concd. HCl iron/Concd. HCl, Zinc-Concd. HCl, preferably stannous chloride/Concd. HCl
The polar solvent used in step (iii) may be selected from n-propanol, isopropanol, ethanol, n-butanol or their mixtures preferably n-butanol.
The base such as potassium hydroxide or sodium hydroxide preferably may be used in step (iv) and the temperature may be at the range of 90-95 deg C.
According to yet another embodiment of the present invention there is provided an alternative process for the preparation of the compounds of the general formula I as defined above
Accordingly the present invention provides a process for the preparation of compounds of the general formula I as defined above which comprises                (i) Preparing N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (XVII)        
by conventional methods.                (ii) Condensing N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (XVII) with trifluoro methyl aroyl chlorides of the formula (XII) to yield the novel compounds of general formula (I) where [Y, n, X are as defined above]        
The compounds of the formula (I) as defined above inhibit Bcr-abl Kinase and are thus, as explained above, suitable for the treatment of Bcr-abl positive cancer and tumor diseases, such as leukemias (especially Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia, where especially apoptotic mechanisms of action are found)
The invention also relates to pharmaceutical compositions comprising an affective amount, especially an amount effective in the prevention or therapy of one of the abovementioned diseases, of the active ingredient together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parental administration, and may be inorganic or organic, solid or liquid. In addition to the active ingredient(s), the pharmaceutical compositions of the present invention may contain one or more excipients or adjuvants. Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel(R)), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit(R)), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form, such as capsules may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel(R)), hydroxypropyl methyl cellulose (e.g. Methocel(R)), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon(R), Plasdone(R)), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol(R), Primellose(R)), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone(R)), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab(R)) and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
When a dosage form such as a capsule is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
Solid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification
The details of the invention are provided in the Examples given below which are provided to illustrate the invention only and therefore they should not be construed to limit the scope of the invention